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Abstract

Introduction

Cefepime has been associated with a greater risk of mortality than other beta-lactams
in patients treated for severe sepsis. Hypotheses for this failure include possible
hidden side-effects (for example, neurological) or inappropriate pharmacokinetic/pharmacodynamic
(PK/PD) parameters for bacteria with cefepime minimal inhibitory concentrations (MIC)
at the highest limits of susceptibility (8 mg/l) or intermediate-resistance (16 mg/l)
for pathogens such as Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus. We examined these issues in a prospective non-interventional study of 21 consecutive
intensive care unit (ICU) adult patients treated with cefepime for nosocomial pneumonia.

Methods

Patients (median age 55.1 years, range 21.8 to 81.2) received intravenous cefepime
at 2 g every 12 hours for creatinine clearance (CLCr) ≥ 50 ml/min, and 2 g every 24 hours or 36 hours for CLCr < 50 ml/minute. Cefepime plasma concentrations were determined at several time-points
before and after drug administration by high-pressure liquid chromatography. PK/PD
parameters were computed by standard non-compartmental analysis.

Results

Seventeen first-doses and 11 steady states (that is, four to six days after the first
dose) were measured. Plasma levels varied greatly between individuals, from two- to
three-fold at peak-concentrations to up to 40-fold at trough-concentrations. Nineteen
out of 21 (90%) patients had PK/PD parameters comparable to literature values. Twenty-one
of 21 (100%) patients had appropriate duration of cefepime concentrations above the
MIC (T>MIC ≥ 50%) for the pathogens recovered in this study (MIC ≤ 4 mg/l), but only 45 to 65%
of them had appropriate coverage for potential pathogens with cefepime MIC ≥ 8 mg/l.
Moreover, 2/21 (10%) patients with renal impairment (CLCr < 30 ml/minute) demonstrated accumulation of cefepime in the plasma (trough concentrations
of 20 to 30 mg/l) in spite of dosage adjustment. Both had symptoms compatible with
non-convulsive epilepsy (confusion and muscle jerks) that were not attributed to cefepime-toxicity
until plasma levels were disclosed to the caretakers and symptoms resolved promptly
after drug arrest.

Conclusions

These empirical results confirm the suspected risks of hidden side-effects and inappropriate
PK/PD parameters (for pathogens with upper-limit MICs) in a population of ICU adult
patients. Moreover, it identifies a safety and efficacy window for cefepime doses
of 2 g every 12 hours in patients with a CLCr ≥ 50 ml/minute infected by pathogens with cefepime MICs ≤ 4 mg/l. On the other hand,
prompt monitoring of cefepime plasma levels should be considered in case of lower
CLCr or greater MICs.

Introduction

An empiric study in which the pharmacokinetics (PK) of imipenem were prospectively
monitored in intensive care unit (ICU) children revealed wide inter-individual variations
(up to four-fold at peak and >10-fold at through concentrations) that resulted in
potentially too low dosages in 30% of cases [1]. Similar observations were also made with imipenem in adult patients [2,3], suggesting that drug adjustment algorithms used at the bedside might not be always
accurate in unstable ICU patients, and that drug monitoring should be used more often
[1].

The present report describes a similar quality assessment study in which the PK of
cefepime was monitored in ICU adult patients. As in the children's study alluded to
above [1], PK results were not disclosed to the caretakers unless clinical problems were suspected
to be associated with inappropriate drug dosages. This observation is timely in light
of two meta-analyses that reported an increased mortality (risk ratio 1.26 (95% CI
1.08 to 1.49)) in patients treated for severe infection with cefepime, as compared
to patients treated with other beta-lactams [4,5]. Moreover, Bhat et al. [6] observed that bacteremia due to gram-negative pathogens with minimal inhibitory concentrations
(MICs) of cefepime in the highest range of susceptibility (that is, 8 mg/l) or above
[7] were associated with an increased mortality in patients treated with cefepime than
in those treated with other antibacterials.

Alarmed by these reports, the Food and Drug Administration (FDA) completed a complementary
meta-analysis of 88 comparative studies (including the 38 reported by Yahav et al)
totalizing 9,467 cefepime-treated patients [8]. This analysis did not confirm a higher overall mortality related to cefepime. Nevertheless,
in the absence of drug monitoring, the excess mortality or treatment failures reported
in specific studies [4-6] could be related to untoward overdosing or underdosing of cefepime in unstable patients.

Ideal dosing of cefepime should obey pharmacokinetic/pharmacodynamic (PK/PD) population
kinetics that help adjust drug dosing to the most appropriate PK/PD profile against
target organisms [9-14]. This corresponds to a period of drug concentration above the MIC (T>MIC) of >40% to 60% for beta-lactams in general [15-20] and ≥50% for cefepime [19,20]. However, whether these goals are reached in the empiric day-to-day clinical setting
is uncertain, especially in unstable ICU patients. The present work examined these
issues in 21 consecutive ICU adult patients treated with cefepime. Individual PKs
were prospectively determined following a similar study design as for imipenem in
children [1]. The results further strengthen the need for antibiotic monitoring in complicated
clinical situations.

Materials and methods

Experimental design

The Centre Hospitalier Universitaire Vaudois (CHUV) is a 1,400-bed tertiary teaching
hospital encompassing all medical and surgical disciplines including organ grafts
and burn patients. Its ICU is a mixed medico-surgical facility of 32 beds with a rate
of admissions of approximately 2,600 patients per year. The study was aimed at following
the natural PK profiles of cefepime in ICU adult patients, in a setting where beta-lactam
monitoring was not routinely performed. It followed a similar protocol as in our former
study of imipenem PK in the pediatric ICU [1]. In brief, all consecutive adult patients (≥18 years old) entering the ICU and prescribed
cefepime (Bristol-Myers Squibb AG, Baar, Switzerland) by the caretakers were prospectively
enrolled. All drug dosages and dosing-adjustments were decided by them, based on daily
clinical and laboratory assessments. Patients were excluded if they were allergic
to beta-lactams, had been treated with cefepime within the last 15 days, or were requiring
dialysis at the time of inclusion. The results of cefepime monitoring were not disclosed
to the caretakers until the end of the study, unless the caretakers or the principal
investigators (TMC and PM) suspected clinical problems that might be associated with
inappropriate drug concentrations [1]. The study aimed at collecting a total of 20 patients. The protocol was accepted
by the local ethic committee, and written consent was obtained from the patient or
from her or his legal representative.

Cefepime dosage in the ICU is 2 g every 12 h in patients with creatinine clearance
(CLCr) ≥50 ml/minute, and 2 g every 24 h or more in patients with CLCr < 50 ml/minute. CLCr was calculated by the Cockcroft-Gault equation [21]. CLCr values reported herein are only those measured concomitantly to the determination
of cefepime PKs. The drug was infused over 30 minutes via an intravenous line. PK
analyses were performed at the first-dose and/or at steady state, that is, between
Days 4 and 6 after treatment onset. Blood samples were drawn from a site remote from
the drug administration line. In patients receiving the drug every 12 h, samples were
collected just before drug administration, and at 30 minutes, 45 minutes, 1.5, 2.5,
4, 8 and 12 h after the beginning of drug infusion. In patients receiving the drug
at longer intervals, in case of drug adaptation, blood sampling was made.

Determination of cefepime concentrations in the plasma

Cefepime titration was performed as reported in a previous work [22]. Accordingly, to prevent ex-vivo drug degradation, blood samples were immediately
chilled, centrifuged, and stored at -80°C until dosage was performed. All subsequent
processes were performed at 4°C, including automatic injection by a refrigerated autosampler
(Peltier cooler; Labsource, Reinach, Switzerland). Briefly, the procedure included
initial extraction by protein precipitation, followed by reversed phase chromatography
using 0.2 M Borate-Methanol (93%/7% vol/vol) mobile phase and integration of the 260
nm absorption signals. Calibration standards from 0.5 to 200 mg/l were prepared in
healthy volunteer's plasma with cefepime provided by Bristol-Myers-Squibb AG (Sermoneta,
Italy). Assay was carried out with a HPLC Merck-Hitachi LaChrom system (Hitachi Instruments,
Ichige Hitachinaka, Japan)), and a LC18 150 × 4.6 mm column (Supelco, Bellefonte, PA, USA). More details on the method have
already been published elsewhere [22]. Its limit of quantification is of 0.5 mg/l and the intra and inter run coefficients
of variation are below or at 10.3%.

PK parameters

Calculated PK parameters included the terminal slope of cefepime elimination from
the plasma (Kβ), the area under the curve of cefepime plasma concentrations (AUC; 0 to 12 h), the
area under the first moment curve (AUMC), the terminal half-life of cefepime in the
plasma (T1/2β = log 2/Kβ), the mean resident time (MRT = AUMC/AUC), the systemic clearance (CLCEF = dose/AUC), and the initial and steady state volumes of distribution (Vβ = CLCEF/Kβ and Vss = CLCEF × MRT, respectively). For the seven-paired kinetics, comparisons between the first-dose
PK and the steady-state PK were done by the Wilcoxon matched pairs test.

Table 1. Clinical and microbiological features of the study population (10 females and 11 males;
median age 55.1 years, range 21.8 to 81.2)

Presumed pathogens were identified at the central microbiology laboratory of the hospital
and MICs of cefepime were determined by the E-test (AB Biodisk, Solna, Sweden). The
T>MIC period is one of the most pertinent parameters predicting beta-lactam efficacy [15-20]. Therefore, this PK/PD parameter was computed for any kinetics provided by this study,
using the cefepime MIC susceptibility breakpoints recommended by the Clinical and
Laboratory Standards Institute (CLSI) (that is, ≤8 mg/l for Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus, ≤2 mg/l for Haemophilus spp. and ≤1 mg/l or lower for Streptococcus pneumoniae and other streptococci) [7].

Evaluation endpoints

The primary endpoints were the appropriateness of the PK/PD profiles in terms of T>MIC regarding the recommended cefepime MIC breakpoints [7], as well as clinically-detected toxicity. The secondary endpoint was the fact that
patients could be discharged from the ICU and eventually leave the hospital. On the
other hand, treatment success was not a formal endpoint, as the study protocol was
not designed to evaluate cefepime efficacy strico sensu. Cefepime was mostly used as first-line empiric treatment, and caretakers were free
to switch to more standard therapy after receiving the results of microbial identification
and susceptibility tests.

Results

Patient characteristics

Ten females and 11 males (median age 55.1 years, range 21.8 to 81.2) entered the study
between 1 April and 30 September 2001. All consecutive eligible patients were included,
and no patients were excluded after entry. Demographic details and laboratory features
are presented in Table 1. Only patients with clinical and radiological features compatible with nosocomial
pneumonia (as defined by onset of ≥48 h after hospitalization) were included. This
bias toward nosocomial pneumonia is likely to result from the empiric nature of the
study. Indeed, consecutive patients were included by the caretakers, who preferentially
used cefepime monotherapy for empiric treatment of nosocomial pneumonia (we have notoriously
few methicillin-resistant Staphylococcus aureus in our institution), while empirical treatment of other severe infections, mostly
intra-abdominal, involves beta-lactams with anti-anaerobe activities (that is, penems
or penams) sometimes combined with other drugs. Presumed bacterial pathogens cultured
from bronchiolo-alveolar lavage were identified in 10/21 (47%) patients. They were
all susceptible to cefepime according to the standard MIC cut-off values (Table 1) [7].

Cefepime PK profiles

Seventeen first-dose and 11 steady-state PK profiles were determined, among which
both profiles were obtained in seven patients. Eleven patients had only first-dose
PK determinations because they had already left the ICU by the time steady-state measurements
should have been performed (that is, four to six days after treatment initiation).
Conversely, four patients had only a steady-state measurement because they gave their
written consent after the first dose had already been administered. The 12 h administration
schedule was pursued in 19 patients and adapted in two patients with CLCr <50 ml/minute (Figure 1). Figure 1 depicts the kinetics of cefepime concentrations in the plasma versus time at the
first-dose (left panel) and at steady-state (right panel), respectively. Cefepime
concentrations varied by two- to three-fold at peak levels and up to 40-fold at trough
levels (Figure 1 and Table 2). The majority of patients (that is, 13/17 or 76% at first dose and 9/11 or 81% at
steady state) had trough levels ≤10 mg/l. On the other hand, four patients clustered
above this limit at the first dose, and two patients with altered renal function remained
above this value at steady state, in spite of increasing the intervals of drug administration
to 24 h and 36 h, respectively (right panel of Figure 1). These are the two patients who developed untoward neurological side effects.

PK parameters were stable in most patients, with the notorious exception of the two
patients with altered renal function (CLCr = 19 and 12 ml/minute, respectively). Table 2 shows that patients with conserved renal function (that is, a CLCr ≥50 ml/minute) had relatively comparable PK parameters as compared to those previously
reported in healthy volunteers or burn patients. The main difference in our cohort
was a greater T1/2β (h) and a parallel increased mean residence time (MRT).

Factors influencing PK profiles

To further dwell on factors influencing cefepime kinetics we attempted to match clinical
and laboratory co-variables with specific PK parameters. Some associations were straightforward,
such as the direct correlation between ClCr and the steepness of the slope of elimination of cefepime from the plasma (that is,
the terminal slope of cefepime clearance, or Kβ, which follows the steeper slope of initial rapid drug distribution, or Kα) (Figure 2A, B), and between hemodilution and volume of distribution (Vβ) (Figure 2C). These are also the parameters most likely to be taken into account for drug dosing
adjustment by clinicians.

Figure 2.Significant correlations between physiological and pharmacokinetic parameters. Cefepime elimination closely correlated with creatinine clearance (panels A and B), as abundantly described [15-20]. In addition, more intricate parameters also showed independent negative and positive
correlations with drug elimination, as for instance the concentrations of hemoglobin
(panel C) and plasma albumin (panel D). Corresponding coefficients of correlations (r values) are indicated. Additional
correlations are presented in Table 3.

Table 3 presents some of these parameters. Although several are easily associated with hemodynamic
conditions, others could be more intricately involved in drug elimination, as exemplified
by the reported pH-dependent, plasma-dependent, and temperature-dependent degradation
of cefepime [22,24,25]. In this line, both the pCO2 and the HCO3 were significantly associated with decreased drug half-life and mean resident time.
Thus, in complex clinical situations the PK profiles might be influenced by individual
physiopathological variables that are not taken into account in standard algorithms
for adjustment of drug dosages.

Side effects

The protocol was not aimed at detecting specific side effects of cefepime therapy.
Therefore, possible related side effects were left on the appreciation of the caretakers,
based on daily complete clinical and laboratory assessments. No untoward side effects
were attributed to cefepime by the caretakers at first. Yet the two (10%) patients
with high concentrations of cefepime in the plasma (highest concentrations in right
panel in Figure 1) presented episodes of confusion and flapping tremor compatible with metabolic encephalopathy.
Both had altered renal functions and had been subjected to dosing adjustment (2 g
of cefepime q 24 h and 36 h for the patients with CLCr of 19 and 12 ml/minute, respectively). Yet, this dosage adjustment was insufficient
and they had nevertheless high plasma levels. The accumulation of cefepime in the
plasma concentrations was disclosed to the medical staff, and both patients recovered
within 24 h of treatment arrest.

Pharmacodynamic profiles and clinical outcome

Optimal beta-lactam efficacy requires T>MIC of >60% to 70% for Enterobacteriaceae and streptococci, and 40 to 50% for Staphylococcus aureus [15-19,26]. For certain beta-lactams including cefepime, a lower limit of 50% was also suggested
[19,20]. Table 4 presents the T>MIC of the present patient population as determined for cefepime MICs of 4 and 8 mg/l,
respectively. At the dosage used herein (that is, 2 g q 12 h in patients with CLCr ≥50 ml/minute) all patients had T>MIC values above 50% for cefepime MIC of ≤ 4 mg/ml. Thus, the theoretical PD coverage
was appropriate for all the presumed pathogens recovered in this study (cefepime MIC
≤4 mg/l). All patients in this study were discharged from the ICU without antibiotic
treatment failure regarding the indication of cefepime treatment, and all except one
(Table 1) could eventually leave the hospital. On the other hand, when increasing the cefepime
MIC cut-off to 8 mg/ml, T>MIC decreased to ≤67% at the first dose and <44% at steady state, indicating that the
dosage would be inadequate in a substantial number of patients infected with Gram-negative
pathogens with such borderline susceptibilities, as suggested by Bhat et al. [6].

Table 4. Time over MIC (T>MIC) of total cefepime in patients without renal failure (CLCr > 50 ml/minute)

Discussion

The present empirical study confirms the great inter-individual variability of cefepime
PK in the clinical setting, as reported with cefepime and imipenem by others [1,2,27,28]. Moreover, it underlines the difficulty of bedside prediction of cefepime PK, based
on standard drug adjustment algorithms, including calculated CLCr. In the present series, this resulted in extreme cefepime concentrations in the plasma
from rather low values (trough cefepime concentrations below 4 mg/l in ca 50% of the
patients) (Figure 1) to unpredicted toxic values in two other patients with renal impairment.

A major parameter for cefepime drug adjustment is CLCr, which is often calculated by the classical Cockcroft-Gault equation [21]. However, calculated clearance may be subject to errors because it does not take
into account features such as muscular mass and turnover, which may influence creatinine
concentrations in the serum [29]. Therefore, biases in calculated CLCr could be one potential explanation for the inter-individual PK variability observed.
Nevertheless, although the Cockcroft-Gault equation may suffer from inaccuracies,
the calculated CLCr values correlated very well with cefepime clearance, as indicated in Figure 2. Additionally, we also tentatively calculated CLCr values using the MDRD (Modification of Diet in Renal Disease) method [30], but the results were quite concordant with the values presented herein (data not
presented). Hence, some of the variations might be due to other factors.

For instance, some patients had increased CLCr as previously reported (>120 ml/minute, Figure 2) [31] and might have benefited from increasing drug dosages. Alternatively, additional
more intricate parameters presented in Table 3 might also interfere. Among these, some relations were expected, such as the direct
correlation between ClCr and cefepime elimination, whereas others were less obvious, such as the direct correlation
between the concentration of plasma albumin and Kβ (Figure 2D). Depending on the circumstances, high plasma albumin may be associated either with
dehydration, which could result in poor renal perfusion and decreased cefepime clearance,
or with good cardiovascular performance and good cefepime clearance, which was likely
to be the case herein.

Other parameters for initial dosing are weight and gender, which might call less attention
by the caretakers in adult than in pediatric medicine. However extreme weights in
our series varied by three times (Table 1) and were not likely to explain the up to 40-times difference in drug levels observed.
Moreover, similar variations were observed in other PK studies [2,3], and especially in children, where weight is a prime consideration in drug dosing
decision [1]. Taken together, the extreme variations observed are likely to result from intricate
interactions between multiple factors, which are by no way simple to integrate in
the bedside decision process.

Most patients with a preserved renal function had stable individual PK profiles over
time in spite of a wide range of CLCr values ranging from 160 to 53 ml/minute (Figure 2), and the fact that no drug adjustments were performed. In contrast, drug accumulation
and toxicity was observed in two patients with renal impairment (CLCr < 50 ml/minute), in spite of drug adjustment. This is potentially important because
caretakers did not attribute neuropsychological alterations, which may be multi-factorial
in ICU conditions, to drug toxicity until the high concentrations of cefepime were
disclosed to them and the symptoms resolved promptly after treatment arrest. Moreover,
there is a lack of information in the literature regarding the threshold of cefepime
plasma levels predicting neurotoxicity. Indeed, out of 35 patients with cefepime-induced
neurological complications reported in 10 studies (excluding reviews and chronic dialysis
patients) [27,28,32-39], the concentrations of cefepime were determined in only one case (in the plasma and
the CSF) and were quite high, that is, 284 mg/l and 18 mg/l, respectively [28]. Besides, only one recent study in neutropenic patients with mild renal failure indicated
that trough plasma concentrations of cefepime above 22 mg/l were likely to be associated
with encephalopathy [40]. The main constant over all the reported cases is the association of neurotoxicity
with renal impairment. While renal impairment implies possible drug accumulation,
it might also potentiate the effect of additional neurotoxic factors, including factors
related to the patient, or maybe the C-3' substituent N-methylpyrrolidine metabolite of cefepime, which may accumulate in the case of renal
failure [25,41]. Thus, the threshold of toxicity might be patient-dependent. On the other hand, most
studies examining the PK produced by 2 g of the drug administered intravenously or
intramuscularly to healthy volunteers or patients without renal failure report trough
cefepime concentrations in the plasma ≤10 mg/l in [9,11,42-46], which was also the case herein. Therefore a safe assumption is that trough concentrations
of >10 mg/l of cefepime should alert the clinician on the risk of neurotoxicity in
susceptible patients, and concentrations of >20 mg/l should probably be avoided.

On the other extreme, too low dosages may result in treatment failures, at least as
predicted by PK/PD studies [15-19,26]. Postulating that T>MIC measured is pertinent to predict clinical outcome, then all of our patients had appropriate
coverage of cefepime (T>MIC ≥ 50%) as recently proposed [19,20] for the presumed bacterial pathogens recovered herein (MIC ≤ 4 mg/l) (Table 4). On the other hand, if one postulates an MIC of 8 mg/l, which was associated with
treatment failures in patients with bacteremia due to Gram negative pathogens [6], then close to 50% of the patients would have had an inappropriate coverage (T>MIC > 50%). This is of particular concern when considering problematic pathogens such
as those producing extended-spectrum beta-lactamases, or P. aeruginosa and Acinetobacter spp., which may have high cefepime MICs (≥8 mg/l) and pose major therapeutic challenges,
and if one takes into account that up to 20% of the total drug is bound to serum proteins
[47,48]. Moreover, in addition to pure MIC concerns, a recent study identified P. aeruginosa infection, mechanical ventilation, and neutropenia as independent risk factors for
cefepime treatment failure [49]. Higher cefepime doses were proposed to overcome some of these issues (for example,
2 g q 8 h) [9], but high doses may also increase the risk of neurological side effects. Hence, adjusting
dosage on the basis of drug monitoring is reasonable in such cases.

Conclusions

Taken together, these results of drug monitoring independently validate the population
kinetics of cefepime elaborated by others [9-14]. Moreover, they show that empirical drug dosing following standard drug adjustment
algorithms in the ICU is not accurate enough to prevent extreme PK deviations, which
might be one or the possible explanations for the toxicity and treatment failure problems
reported by Yahav et al. [4] and Bhat et al. [6]. Eventually, they indicate that 2 g of cefepime q 12 h is safe and effective for
patients with CLCr ≥ 50 ml/minute and against pathogens with cefepime MICs ≤ 4 mg/l, but that drug monitoring
should be considered in any conditions falling outside these limits.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

TMC collected the data. TMC, EG, DB and PM initiated the study, and the design. TMC,
DB and PM were involved in the interpretation of the results. TMC wrote the manuscript,
DB and PM helped to draft the manuscript. EG, PAM, RC, MDS, MMB and LD contributed
to the conception of the study and revision of the manuscript. PM and DB provided
the final revision of the manuscript. SB provided technical support for the study.
All authors read and approved the final manuscript.

Acknowledgements

This work was partially supported by an unrestricted grant from Bristol-Myers Squibb.
We would like to thank Willy Lanker for stimulating discussion and Marlyse Giddey
for outstanding technical support, and the medical and nursing staff of the Department
of Adult Intensive Care.

McKinnon PS, Paladino JA, Schentag JJ: Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory
concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious
bacterial infections.